Work

The Conserved Sonic Hedgehog Limb Enhancer Consists of Discrete Functional Elements that Regulate Precise Spatial Expression

Year: 2017

Type: article

Abstract: Expression of sonic hedgehog (Shh) in the limb bud is regulated by an enhancer called the zone of polarizing activity regulatory sequence (ZRS), which, in evolution, belongs to an ancient group of highly conserved cis regulators found in all classes of vertebrates. Here, we examined the endogenous ZRS in mice, using genome editing to establish the relationship between enhancer composition and embryonic phenotype. We show that enhancer activity is a consolidation of distinct activity domains. Spatial restriction of Shh expression is mediated by a discrete repressor module, whereas levels of gene expression are controlled by large overlapping domains containing varying numbers of HOXD binding sites. The number of HOXD binding sites regulates expression levels incrementally. Substantial portions of conserved sequence are dispensable, indicating the presence of sequence redundancy. We propose a collective model for enhancer activity in which function is an integration of discrete expression activities and redundant components that drive robust expression.

Source: Cell Reports

DOI: 10.1016/j.celrep.2017.07.037

Authors: Laura A. Lettice, Paul Devenney, Carlo De Angelis, Robert E. Hill

Institutions: Institute of Genetics and Cancer, MRC Human Genetics Unit, University of Edinburgh

Language: English

Topic: Genomics and Chromatin Dynamics

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: gold

Estimated APC paid: $5,896

Funder: Medical Research Council